New tetracyclic azepine derivatives



United States Patent Ofifice Patented Sept. 4, 1962 3,052,689 NEW TETRACYCLIC AZEPINE DERIVATIVES Walter Schindler, Riehen, near Basel, Switzerland, assignor to Geigy Chemical Corporation, Ardsley, N.Y., a corporation of Delaware No Drawing. Original application Mar. 28, 1960, Ser. No. 17,780. Divided and this application Mar. 9, 1961, Ser. No. 109,471 Claims priority, application Switzerland Mar. 26, 1959 4 Claims. (Cl. 260-319) wherein X represents hydrogen, a halogen atom or a low molecular alkyl radical,

Y represents hydrogen, a halogen atom or a low molecular alkyl radical, and X and Y can be different from each other but when they are the same they are advantageously in the same relative position to the NH group,

-R represents hydrogen or a low molecular alkyl radical,

and

Hal represents bromine or chlorine,

can be converted by treatment with a Friedel-Craft-s condensing agent, in particular aluminium chloride, into 1- oxo 1.2.6.7 tetrahydro indolo[l.7a.7 -a.b]benzo[f] azepines of the general formula which compounds are important new starting materials for the synthesis of valuable pharmaceuticals.

It has surprisingly been found that l-oxo-2-tert.aminoalkyl-l.2.6.7 tetrahydro indolo[l.7a.7 a.b]benzo[f] azepines of the general formula CHI-CH2 9 4 R represents a low molecular alkyl radical,

Am represents a low molecular dialkylamino group the alkyl radicals of which can also be bound to each other direct, and

n represents a whole number of 1 to 3,

which are produced from such starting materials, have valuable pharmacological properties.

The new azepine derivatives of the general Formula III are produced by condensing a compound of the general 5 Formula II in which X and Y are hydrogen atoms and R is a low molecular alkyl radical, either with formaldehyde and bases of the general formula 10 wherein Am has the meaning given above, or by condensing compounds of the general Formula II as mentioned above, in the presence of acid binding agents, with reactive esters of basic alcohols of the general formula LID-(CH Am V 15 wherein Am has the meaning given above and m is 2 or 3.

The 0X0 compounds of the general formula III can then be reduced by means of alkaline earth metal hydrides, in particular lithium aluminium hydride, to 2-tert. aminoalkyl 1.2.6.7 tetrahydro indolo[l.7a.7 ab] benzo [f] azepines of the general formula N H il-(CH2)n-Am iv v1 wherein R, Am and n have the meanings given under Formula lII.

Similar to the compounds of the general Formula III, the compounds of the general Formula VI also possess valuable pharmacological properties, in particular antiallergic and spasmolytic activity with, at the same time, a very slight sedative side effect and they are suitable for the peroral and parenteral treatment of mental disorders and allergy.

That the starting materials of the general Formula II are formed from the compounds of the general Formula I by reaction according to Friedel-Crafts is all the more surprising as the analogous ring closure in other tricyclic N-hetero compounds such as carbazole, dihydroacridine and phenthiazine is not known.

The treatment of compounds of the general Formula I with a Friedel-Crafts condensing agent can be performed, for example, by mixing these compounds with such a condensing agent, in particular, with aluminium chloride, and heating the mixture to temperatures of between -200 C. until the hydrogen halide development ceases. Suitable compounds of the general Formula I are, for example, 5-chloroacetyl-, 5-bromoacetyl-, 5-(a-chloropropionyl)-, 5-(a-bromopropionyl)-, 5-(a-bromobutyryl)-, 5-(a-bromovaleryl)-, 5-(u-bromoisovaleryl)- and 5-(a-bromocaproyl)- iminodibenzyl, -3-chloroiminodibenzyl, -3-bromoiminodibenzyl, -3-ethyliminodibenzyl, -3.7-dichloroiminodibenzyl and -3.7-dimethyliminodibenzyl.

The condensation according to the invention of the starting materials of the general Formula II obtained in this manner, in which X and Y are hydrogen atoms and R is a low molecular alkyl radical, with formaldehyde and an amine of the general Formula IV is performed advantageously in an aqueous organic solvent, e.g. in dioxan, using aqueous formaldehyde solution and acetic acid. The reaction frequently occurs even at room temperature or then at a moderately raised temperature. Examples of amines of the general Formula IV are dimethylamine, diethylamine, di-n-propylamine, di-n-butylamine, di-iso- 0 gutylamine, methyl-n-butylamine, pyrrolidine and piperi- The condensation of l-oxo-l.2.6.7-tetrahydroindolo [1.7a.7-a.b]benzo[f]azepines of the general formula II with reactive esters of basic alcohols of the general Formula V is performed advantageously in the presence of those acid binding agents which are capable of replacing a hydrogen atom of the reactive methylene .group by a metal atom. Examples of such agents are sodium amide, lithium amide and potassium amide as well as lithium, sodium and potassium and alcoholates thereof. As inert organic solvent, in particular, a benzene hydrocarbon such as benzene, toluene or xylene can serve as reaction medium and the reaction can be performed, for example at the boiling temperature thereof.

Suitable reactive esters of amino alcohols of the general Formula V are, in particular, the halides, also for example, aryl sulphonic acid esters and salts of acid esters of sulphuric acid. Examples of suitable halides are:

Dimethylaminoethyl chloride, diethylaminoethyl chloride, methylethylaminoethyl chloride, ,B-dimethylaminopropyl chloride, fl-dimethylaminoisopropyl chloride, 'y-dimethylarninopropyl chloride, ,B-(di-n-propylamino)-ethyl chloride, fl-(methylisopropylamino)-ethyl chloride, fi-(di n-butylamino)-ethyl chloride, B-(di-isobutylamino)-ethyl chloride, pyrrolidino-ethyl chloride, piperidino-ethyl chloride and y-piperidino-propyl chloride as well as the corresponding bromides and iodides.

A particularly suitable reducing agent is lithium aluminium hydride in diethyl ether or in another usual etherlike solvent such as, e.g. tetrahydrofurane.

The tertiary bases of the general Formulae HI and VI form salts, some of which are water soluble, with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane disulphonic acid, acetic acid, citric acid, malic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, benzoic acid and phthalic acid.

The following examples further illustrate the production of the new compounds. Parts are given therein as parts by weight and their relationship to parts by volume is as that of grammes to cubic centimetres. The temperatures are in degrees centigrade.

EXAMPLE 1 (Production of the Starting Material) (a) 98 parts of iminodibenzyl are dissolved in 300 parts by volume of benzene and 116 parts of m-bromobutyric acid bromide are added. The mixture is refluxed for 5 hours and then the solvent is distilled off in the vacuum. The remaining 5-(a-bromobutyryl)-iminodibenzyl crystallises from ether, M.P. 100. In an analogous manner on using 108 parts of a-bromopropionic acid bromide, 5- (ot-bromopropionyl)-iminodibenzyl is obtained, M.P. 118- 1 19 (b) 40 parts of the above bromine compound and 40 parts of aluminium chloride are Well mixed and heated in an oil bath at 160. On completion of the exothermic reaction, the reaction mixture is cooled and poured onto ice and a little hydrochloric acid. The reaction product is taken up in ether, the aqueous phase is thoroughly extracted with ether, the combined ether solutions are washed with water and concentrated. The residue crystallises from a little ether. l-oxo-2-ethyl-1.2.6.7-tetrahydroindolo[1.7a.7-a.b]benzo[f] azepine is obtained which melts at 108. 1-oxo-2-methyl-1.2.6.7-tetrahydro-indolo [,1.7a.7-a.b]benzo[f]azepine (M.P. 108-109) and l-oxo- 1.2.6.7 tetrahydro indolo[1.7a.7 a.b]benzo[f]azepine (M.P. 198) are obtained in an analogous manner.

EXAMPLE 2 20 parts of the 2-ethyl compound obtained according to Example 1(b) are dissolved in 90 parts by volume of dioxan and the solution is added dropWise at 0-5 to 51 parts by volume of glacial acetic acid, 11 parts by volume of formaldehyde and 14 parts by volume of 40% aqueous dimethylarnine in 90 parts by volume of dioxan. The solution is stirred for 16 hours at room temperature, then poured into excess water and is washed with ether. The aqueous phase is then made alkaline with concentrated ammonia solution, the precipitated oil is taken up in ether and the ether solution is dried and concentrated. On adding alcoholic hydrochloric acid to the remaining oil, the hydrochloride of 1-oxo-2-ethyl-2-dimethylaminomethyl- 1 .2.6.7-tetrahydro-indolo 1 .7a.7-a.b] benzo [f] azepine is obtained. M.P. 228-230.

On using the corresponding starting materials:

EXAMPLE 3 The ethereal solution of 18 parts of the base obtained according to Example 2 in 100 parts of ether is added dropwise to the boiling solution of 4.3 parts of lithium aluminium hydride in 300 parts by volume of ether and the whole is then refluxed for 22 hours. The reaction mixture is then cooled, carefully decomposed with water and the ethereal phase is removed. The basic parts are removed from the ethereal phase by extracting three times with dilute acetic acid. The combined acid extracts are made alkaline and extracted with ether. On adding alcoholic hydrochloric acid to the ether extract, the sparingly soluble hydrochloride of 2-ethyl-2-dimethylaminomethyl- 1.2.6.7-tetrahydro-indolo l.7a.7-a.b]benzo [f] azepine precipitates; M.P. 207-208". 2-methyl-2-diethylaminomethyl 1.2.6.7 tetrahydro indolo[1.7a.7-a.b]benzo[f] azepine hydrochloride (M.P. 197200) and 2-ethyl-2- pyrrolidinomethyl 1.2.6.7 tetrahydro indolo[1.7a.7- a.b]benzo[f]azep ine hydrochloride (M.P. 197198) are obtained in an analogous manner.

EXAMPLE 4 15 parts of 1-oxo-2-ethyl-1.2.6.7-tetrahydro-indolo[l. 7a.7-a.b]benzo[f]azepine (see Example 1(b)) and the base liberated from 12 parts of dimethylaminoethyl chloride-hydrochloride are stirred in benzene at 55-60 and a suspension of 3 parts of sodium amide in toluene is added dropwise. After the dropwise addition, the whole is stirred for 1 hour at 60 and is then refluxed for 16 hours. The reaction mixture is then cooled, decomposed with Water and the basic parts are removed by extraction with diluted hydrochloric acid. The acid extracts are made alkaline and extracted with ether. On adding alcoholic hydrochloric acid to the ethereal solution of the base, the hydrochloride of 1-oxo2-ethyI-Z-dimethylaminoethyl 1.2.6.7 tetrahydro-indolo[ 1.7a.7-a.b]benzo [f] azepine precipitates; M.P. 248-253".

l-oxo-Z methyl-2-('y-dimethylaminopropyl) 1.2.6.7.- tetrahydro-indolo[ 1.7a.7-a. b. ]benzo [f] azepin hydrochloride is obtained in an analogous manner. M.P. 210.

EXAMPLE 5 2 parts of lithium aluminium hydride in 200 parts of anhydrous other are brought to the boil and 9 parts of the 1-oxo-2-ethyl-2-dimethylaminoethyl 1.2.6.7 -tetrahydroindolo[1.7a.7-a.b] benzo[fJazepine obtained according to Example 4 are added dropwise. The reaction mixture is refluxed for 22 hours. On Working up analogously to Example 3, the hydrochloride of 2-ethyl-2-dimethylaminoethyl 1.2.6.7 tetrahydro-indolo[1.7a.7-a.b] benzo[f] azepine is obtained. M.P. 207-208 (from acetone).

The present application is a division of copending application Serial No. 17,780, filed March 28, 19,60.

5 What I claim is: 1. A tetraeyclic compound of the formula Clair-CH2 wherein R represents lower alkyl,

Am represents a member selected from the group consisting of lower dialkylamino and pyrrolidino, and n is an integer from 1 to 3.

2. 2-ethy1-2-dimethylaminomethyl-1.2.6.7-tetrahydro-in- 5 dolo[l.7a.7-a.b]benzo[f]azepine.

3. 2-methy1-2-diethy1aminomethy1-1.2.6.7-tetrahydro-indo10[ 1.7a.7-a.b]benzo f] azepine.

4. 2-ethyl-Z-pyrrolidinomethyl-1.2.6.7-tetrahydro-indolo [1.7a.7-a.b]benzo[f] azepine.

10 References Cited in the file of this patent UNITED STATES PATENTS 2,919,271 Craig et a1. Dec. 29, 1959 

1. A TETRACYCLIC COMPOUND OF THE FORMULA 